The Primary Antibody Repertoire of κ-Deficient Mice is Characterized by Non-Stochastic Vλ1 + VH Gene Family Pairings and a Higher Degree of Self-Reactivity

We have investigated the primary antibody repertoire of genetically manipulated 129/Sv κ-deficient (JC_κD) mice, in order to understand the contributions of the λ-light chain, in the absence of an otherwise predominant κ-light chain, to the development of humoral immunity. The expression of V_λ1 gene (λ₁ and λ₃ subtypes) and the V_λ1 + V_H (J558, 36–60, V_H11 and S107) gene family associations were studied in 7.43 × 10³ mitogen-activated splenic B-lymphocyte clones of JC_κD origin. Furthermore, the functional significance of the exclusive expression of the λ-light chain, in the peripheral B-cell repertoire of JC_κD mice, was analysed by determining natural autoantibody specificities in the circulating serum immunoglobulin and the frequency of autoreactive B-lymphocyte clones in the peripheral B-lymphocyte repertoire. These experiments revealed that: first, of the three available V_λ genes at the λ locus, the V_λ1 gene is the one that is expressed most frequently (59.9%); second, non-random V_λ1 + V_H (J558, 36–60) gene family pairings occur in κ-deficient mice; and third, a higher degree of self-reactivity is generated as a result of exclusive use of the λ-light chain, as evidenced by higher levels of serum natural autoantibodies as well as a high frequency of autoreactive B-lymphocyte clones in κ-deficient (129/Sv JC_κD) mice. These observations suggest that the high murine κ/λ ratio in mice may, apart from high sequence diversity at the κ-locus, be a result of endogenous selection against the λ-light chain to restrict self-reactivity within the homeostatic threshold.